药物合成反应第六章氧化反应

第六章氧化反应氧化反应:使底物增加氧或失去氢的反应第一节烃类的氧化反应苄位、烯丙位及羰基-活性位重要，有实际意义，其他位置则无实际意义，因氧化产物复杂。一苄位烃基的氧化形成醛形成酮形成酸α1形成醛(1)CrO3/Ac2O/H2SO4试剂，先生成二磺酸酯，再水解成醛CrO3/Ac2O/H2SO4(65-66%)CH3NO2CHO(OCCH3)2H2OH2SO4NO2NO2CHO2氯化铬酰(Chromychlorde)CrO2Cl2(1)CrO2Cl2/CCl4(2)H2O(80%)CH3BrBrCHO机理:(离子型)cHHHCrClClOO+CH2OCrCl2OHCrO2Cl2CH(OCrCl2OH)2(Etard复合体)H2OCHO+2H2CrO3机理:(自由型)ArCH3+CrO2Cl2ArCH2HOCrOCl2+ArCH2OCrCl2OHArCH2OCrCl2OH+CrO2Cl2ArCHOCrCl2OH+HOCrOCl2ArCH(OCrCl2OH)2H2OArCHO+2H2CrO3Etard复合体(3)硝酸铈铵[Ce(NH4)2(NO3)6,CAN]选择性好Ce(NH4)2(NO3)6/HClO4400C,80min(92%)CH3CHOCe(NH4)2(NO3)6/50%HAC800C,120min(100%)CH3H3CCH3H3CCH3CHO机理:ArCH3+Ce4+ArCH2+Ce3++H+ArCH2+Ce4++H2OArCH2OH+Ce3+H++ArCHO+2Ce3++2H+2Ce4+ArCH3OH+注:苯环上有-NO2、-X吸电子基时，收率降低。NO2CH3NO2CHOCe4+/HNO3900C,4.5h(4)SeO2试剂CH3CH3CH3SeO2EtOHCH3CH3CHO(82%)2形成羧酸、酮(1)KMnO4、Na2Cr2O7、Cr2O3和稀HNO3作氧化剂KMnO4/NaOH/H2O+CH3SO2NH2350CCOOKONHSO2HSO2NH2(2)空气氧化O2/Co(OAc)2/HBr/HAc2h(91%)BrCH3BrCOOH(3)用硝酸铈铵作氧化剂，苄位亚甲基氧化成酮CAN/HNO3900C,70min(77%)CH3ArCH2CH3ArCO300C,90min(76%)CAN/HNO3O二羰基位活性烃基的氧化1形成-羟酮Pb(OAc)4/BF3O(C2H5)2/C6H6COAcOOCOAcOOCH3CH2OAc250C(86%)αα加BF3有利于羰基的甲基乙酰化HCOCH3CONH2RNO2/tBuOH/tBuOK/P(OC2H5)3-200CHOCOCH3CONH2RN(96%)或用Zn/CH3COOH代替P(OC2H5)3亦可若-H过氧基的碳原子上有H时，可发生碱消除反应，降低了-羟酮的收率。采用过氧化钼MoO5、吡啶、六甲基磷酰胺复合物(MoOPH)作试剂，可以克服上述缺陷。αα-700C-00COC6H5MoOPHOC6H5HO2形成1，2-二羰基化合物SeO2作氧化剂，但-位烃基相同才有合成意义dioxane(69-72%)CH3COSeO2COCHOSeO2/HAc/H2O(100%)890CC6H5C6H5COCH2C6H5COCOC6H5α三烯丙位烃基的氧化1SeO2氧化(机理不要求)遵循如下规则:(1)氧化双键碳上取代基较多的一边的烯丙位烃基CCCH3HH3CH3COSeO2CCCH3HH3CHOH2C(2)在不违背上述规则情况下的氧化顺序:CH2CH3CHCH3CH3CH3CH2CHOHCSeO2CH3CH3CH3CH2CHCCH3CH3CH2CHCCHOH34:1(3)当上述两规则有矛盾时,一般遵循(1)H3CCCH3CHCH2CH3SeO2H3CCCH2OHCHCH2CH3(4)双键在环内时，双键碳上取代基较多一边的环上烯丙位碳氢键被氧化；CH2CH3SeO2CH2CH3HO(5)末端双键氧化时，发生烯丙位重排，羟基引入末端CH3CH2CH2CH2CHCH2SeO2CH3CH2CH2CHCHCH2OH以上为Guillemonat规则(1939)2CrO3-吡啶复合物(Collins试剂)CrO3-吡啶/CH2Cl2(68%)CH3OCH3氧化时发生烯丙双键移位。用铬酸叔丁酯CrO3-t-BuOH也可烯丙位羟基氧化。(60%)AcOOOAcAcOOAcCrO3-t-BuOH3用过酸酯氧化/CuBr(77%)△OOC6H5OCOC6H5COC(CH3)3机理：RCOOOC(CH3)3Cu(CH3)3CO++Cu2+RCOO+(CH3)3CO+(CH3)3COH+RCOO+Cu2+RCOO+Cu+Cu+OCOR注：脂肪族烯烃氧化时，发生异构反作用CuCH3CH2CHCH2CH3CHCHCH3RCOOOC(CH3)3/CH3CHCHCH2OCOR+CH3CHCHCH2OCOR(90%)(10%)原因:RCHCHCH2CuRCHCH2CuCH(稳定性)第二节醇的氧化反应一伯、仲醇被氧化成醛、酮1用铬化合物氧化H2CrO4/H2O/Et2O(85-90%)OHO250CH2CrO4/CH2Cl2/H2O-50C-00C(67-79%)HOOOOHH2CrO4/HAc/MnCl2260C,4hCH3COOOOCH3COOOHO注:(1)CH2Cl2可溶解生成酮，避免深度氧化；(2)MgCl2可除去生成的和(3)Jones可用于对氧化敏感的基团(NH2、C=C、、烯丙位碳氢键)COCr4+Cr5+HOCOCH3H2CrO4/CH3COCH3/H2O0-200COCOCH3CrO3+H2SO4稀释(4)不适合于伯醇氧化(5)机理:+COHCrOHHCrO3OOCO+COHCrOHHCrO3OOCO＞(3:1)HOHHOH＜(1:2)HOHHOH＞(2.5:1)HHOHOH-OH活性e-OHα(6)(7)Sarett试剂、Corwforth试剂及Collins试剂(用于伯醇氧化成醛)CrO3/Py=1/10CrO3/H2O/Py=1/1/10CrO32Py(无水)CrO3/Py(90%)OOOHHOOOOHO250CCollins试剂(80%)(CH2)5CHOCH3CH2OH(CH2)5CH3(85%)NaOAc/CH2Cl2C5H5NHCrO3ClCH2OHOOOOCHO2用锰化合物氧化O伯醇酮，仲醇酮O-C上有氢时，酮收率较低；-C上无氢时，效果好。α(1)KMnO4(100%)CHOHKMnO4CONNαKMnO4/HOAc(100%)C8H17HOC8H17OKMnO4/Mg(NO3)2(66%)CH3OHOHCHCHCH3CH3OHOHCH3CCMnO2/C5H12250C,7d(80%)CH2OHCH3CH3CH3CH3CH3CH3CH3CH3CHOMnO2/CHCl3r.t.(62%)HOHOOHHOOHO(2)新制MnO2MnO2不氧化饱和醇，利用此性质可进行选择性氧化Ag2CO3/硅藻土OHOHOHOC6H63用Ag2CO3氧化Ag2CO3/硅藻土(空阻大，不易被氧化)Ag2CO3/硅藻土HOOHCH3COCH3OOH(烯丙位-OH易被氧化)Ag2CO3/C6H6HOOOHOOCH2OHCH2OHHHOO(1，6或1，5二-OH存在时，易被氧化成内酯)其他二元醇可被氧化成醛或酮。(80%)CH3CHCH2CH2CHCH3CH3CCH2CH2CHCH3OHOAg2CO3OHOH4用DMSO氧化(1)DMSO-DCC(Pfitznor-Moffat氧化)机理:C6H11NCNC6H11+H3CSCH3OHC6H11NHCNC6H11H3CSCH3ORCHROHSOCHRRH3CH3C+(C6H11NH)2COSOCRRH3CH3CHH(CH3)2S+CRROCrO3/Py(90%)OOOHHOOOOHO250Cr.t.DMSO-DCC/CF3COOHHOOOCH3COOCH3COea-OH为e键:Y=99%-OH为a键:Y=6.20%OHOHDMSO-DCC/Py/TFAr.t.(70%)HOOOO(不影响C=C键)TFA=CF3COOHSOH3CH3C+CH3COCOOCH3SOH3CH3CCCH3O+CH3COO机理：SOH3CH3CCR2HR2CHOHPySH3CH3C++R2COHPy(2)DMSO-Ac2O(DCC有毒，难分离)也可发生副反应：R2CHOSCH3CH2HPyR2CHOSCH3CH2R2CHOCH2SCH3另一副反应为醇的乙酰化：使此反应收率降低。-OH在a键上：Y=53%-OH在e键上：Y=13%r.t.4dDMSO-(CH3CO)2OHOOCOOOHCH2OAcOCOOHCH2OAcDMSO-(CH3CO)2OHMPA(70%)(99%)OHOODMSO-Ac2OO用甲磺酸酐(MeSO2)2O代替(CH3CO)2O在六甲磷酰胺中反应，可使副反应降低。+Tol-250COOOCH2NS(CH3)2ClOHCH2S(CH3)2ClEt3NCHOOONS(CH3)2Cl用代替，也可氧化-OH。但对双键有影响。(93%)(1)Cl2/C6H5SCH3/CH2Cl2(2)Et3N(80%)OOHOHOH++i-(PrO)3(Me3CO)3+CH3OCCH3OAlAlR2CHOH+(Me3CO)3AlR2CHOAl(OCMe3)2+Me3COH+CH3CH3OCR2HCOHOAlRRH3COCH3CAlC5Oppennader氧化Al(0-Pr-i)3HOCH3COOOCH3CONBA/CH3COCH3/H2O00C,2hHOOCCH3OOHHOHOOCCH3OHNBA:N-溴代乙酰胺6N-氯代酰胺氧化(只氧化键上的-OH)α(80%)Pt/O2/C7H16CH3CCH3CH2OHCHOCHCH3CCH3CH7Pt/O2氧化(不影响双键，且可使伯醇停留在醛阶段)8Pb(OAc)4氧化R2CHOH+++Pb(OAc)4NR2CHOPb(OAc)3N2HOAc机理:CRROHPb(OAc)2NNOAcCOR+RPb(OAc)2++N2HOAc此复合物不稳定，易发生自由基分解；+R2CHOPb(OAc)3R2CHOPb(OHAc)3OCH3OOHCH3CH3Pb(OAc)4-HOAcPb(OAc)3Pb(OAc)3++CH2OHCH2OHPb(OAc)3CH2OHOAcPb(OAc)2Pb(OAc)2AcOOOHH若位有氢且空间位置合适时，易形成五圆环的醚。αPb(OAc)4/C6H6△OOHAcORRAcO如：++(无水)OHCHOOHPb(OAc)4R2CHOPb(OAc)2R2R1CHCHR1Pb(OAc)4/PyorCH3COOKOHOHCHOCHO二1，2-二醇的氧化1用四醋酸铅氧化OHOHOOPb(OAc)4/TFA顺式比反式易被氧化(60%)机理:(顺式)CCOHOH+Pb(OAc)4HOAcCCOHOPb(OAc)3HOAcCCOOPb(OAc)2(反式)慢快CCOO+Pb(OAc)2Pb(OAc)2B:+HOCCOPbOAcOAcOAcBH+CO2+OAc++++2OOHOHCOHCH5IO6IOOCCOHOHOCHIO3H2O2用过碘酸氧化(反式不被氧化)Na2Cr2O7/HClO4/H2OCH3CH3OOOHOHCH3CH3CrOOOCH3CH3O3用铬酸氧化顺式比反式要快1700倍铬酸(75%)OCHOO1000CCOOH(1)KMnO4/H2O(2)H3O(78-84%)OOCHOOOCOOH第三节醛的氧化一用KMnO4铬酸氧化MeO(1)Ag2O/NaOH(2)HClMeO(83-95%)CHOHOHOCOOHO2/NaOH/CuOAg2O(86-90%)OCHOOCOOH2Ag2O、CuO氧化CH3COOOH/CH3COOH(90%)CHOCOOH3过氧酸氧化(81%)OHOHCOOCHOOHHO